Idiopathic dilated cardiomyopathy (DCM), a heritable disorder causing human heart failure, has been traditionally attributed to mutations in genes encoding contractile and cytoskeletal proteins. Recent human genetic studies have uncovered defects in distinct molecular pathways, indicating that DCM does not exclusively arise from primary mechanical or structural deficits. Despite these advances, the molecular basis for this disorder is unknown in the vast majority of patients with familial and sporadic disease, emphasizing the necessity for further human genetic investigations. This proposal is based on recruitment and phenotypic characterization of 17 multigenerational families with monogenic DCM, suitable for disease gene mapping, and on a cohort of 449 unrelated individuals with DCM. The first aim is to map chromosomal loci for familial DCM. This will be accomplished by genome-wide linkage analysis. The second aim is to define critical subchromosomal regions for the identification and selection of candidate genes for DCM. The third aim is to identify mutations in positional candidate genes that segregate with DCM. Novel genes, once identified, will be screened for to determine the frequency and spectrum of mutations in patients with familial and sporadic DCM. These aims will be achieved by capitalizing on contemporary genomic databases and by utilization of high throughput systems for genotyping, mutation scanning, and DNA sequencing. The overall objective of this work is to provide new insight into the molecular basis of heart failure and to improve prediction, prevention, and treatment of DCM. Relevance to public health: Dilated cardiomyopathy (DCM) is a major public health problem, resulting in heart failure, arrhythmia, and death. DCM is the most common reason for cardiac transplantation, due to lack of diagnostic tests for early detection and ineffective treatments in advanced disease. Discovering the genetic basis of DCM will lead to better ways to diagnose and prevent the progressive weakening of heart muscle that afflicts patients with this disorder.